tbuckley/cabot-search huggingface dataset:
Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma
Authors: Gail M. Gauvreau, Jens M. Hohlfeld, J. Mark FitzGerald, Louis-Philippe Boulet, Donald W. Cockcroft, Beth E. Davis, Stephanie Korn, Oliver Kornmann, Richard Leigh, Irvin Mayers, Henrik Watz, Sarah S. Grant, Monish Jain, Maciej Cabanski, Peter E. Pertel, Ieuan Jones, Jean R. Lecot, Hui Cao, Paul M. O'Byrne
Journal: European Respiratory Journal (2023)

Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma.This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (FENO) were secondary and exploratory end-points.28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). FENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated.Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.
A predictive model for acute exacerbation of idiopathic interstitial pneumonias
Authors: Masato Karayama, Yoichiro Aoshima, Takahito Suzuki, Kazutaka Mori, Nobuko Yoshizawa, Shintaro Ichikawa, Shinpei Kato, Koshi Yokomura, Masato Kono, Dai Hashimoto, Yusuke Inoue, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Tomoyuki Fujisawa, Noriyuki Enomoto, Satoshi Goshima, Naoki Inui, Takafumi Suda
Journal: European Respiratory Journal (2023)

Background Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) induces permanent pulmonary dysfunction and is potentially lethal. The unpredictable occurrence of AE-IIPs remains an important clinical issue in the management of IIPs. Methods In this multicentre, retrospective, observational study, a predictive score for AE-IIPs was designed using clinical factors based on multivariate Fine–Gray analysis in patients with IIPs. Results Based on multivariate Fine–Gray analysis in an exploratory cohort of 487 patients with IIPs, the predictive score for AE-IIPs was determined as follows: 1 point each was added for honeycombing on high-resolution computed tomography (H), age &gt;75 years (A) and lactate dehydrogenase level &gt;222 U·L −1 (L); the total score ranged from 0 to 3 (HAL score). The HAL score discriminated the risk of AE-IIPs with a C-index of 0.62 (95% CI 0.56–0.67); this discrimination was verified in a validation cohort of 402 patients with IIPs with a C-index of 0.67 (95% CI 0.60–0.73). In a combined cohort, the estimated cumulative risks for AE-IIPs at 1, 2, 3, 5 and 10 years were 1.9%, 3.5%, 5.1%, 7.7% and 12.9%, respectively, in the total score 0 group; 4.7%, 8.3%, 12.0%, 17.7% and 28.4%, respectively, in the total score 1 group; and 8.0%, 14.2%, 19.7%, 28.7% and 43.0%, respectively, in the total score ≥2 group. Subgroup analysis revealed that the HAL score was applicable to patients with and without idiopathic pulmonary fibrosis. Conclusions The HAL score discriminated the risk of AE-IIPs and could aid in the management of IIPs.
Author Correction: Diet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination
Authors: Mar Bosch-Queralt, Ludovico Cantuti-Castelvetri, Alkmini Damkou, Martina Schifferer, Kai Schlepckow, Ioannis Alexopoulos, Dieter Lütjohann, Christian Klose, Lenka Vaculčiaková, Takahiro Masuda, Marco Prinz, Kathryn M. Monroe, Gilbert Di Paolo, Joseph W. Lewcock, Christian Haass, Mikael Simons
Journal: Nature Metabolism (2023)
Midterm Echocardiographic Follow-Up After Ross Operation
Authors: Martin Briand, Philippe Pibarot, Jean G. Dumesnil, Paul Cartier
Journal: Circulation (2000)

Background —The pulmonary autograft (Ross) operation is an attractive treatment for aortic valve disease, but hemodynamic follow-up is not well defined. Methods and Results —One hundred thirty-two consecutive patients (62% male, mean age 40±11 years) were followed up to 5 years after the Ross operation. Echocardiography was performed early (within 30 days), 3 to 6 months, and yearly after surgery. The valve effective orifice area (EOA) and mean transvalvular gradient of both aortic and pulmonary valves were measured, and transvalvular regurgitation was assessed by using color Doppler echocardiography. EOA was indexed for body surface area. The hemodynamic performance was excellent for both the aortic and pulmonary valves early after surgery (gradient, 3±4 and 3±4 mm Hg, respectively). It remained stable thereafter for the aortic valve, whereas there was a significant deterioration of the EOA (−0.74±0.82 cm 2 ) and gradient (+6±8 mm Hg) for the pulmonary valve, which occurred mostly during the first 6 months after surgery. This hemodynamic deterioration resulted in suboptimal (defined as an EOA index &lt;0.85 cm 2 /m 2 ) hemodynamics in 19.3% of the patients, to the extent that 3 (2%) of the 132 patients eventually had to be subjected to further surgery for severe pulmonary valve stenosis. Conclusions —The pulmonary autograft provides continued excellent hemodynamics in the aortic position, whereas moderately high gradients can be found across the pulmonary homograft in some patients. Further studies are necessary to identify the factors responsible for the deterioration of the hemodynamic performance of the homograft in the pulmonary position and to determine its impact on right ventricular function and clinical status.
Optimal perioperative therapy for incidental gallbladder cancer (OPT-IN): A randomized phase II/III trial—ECOG-ACRIN EA2197.
Authors: Shishir K. Maithel, Sung Chul Hong, Cecilia Grace Ethun, Cristina R. Ferrone, Flavio G. Rocha, Charles A. Staley, Peter J. O'Dwyer
Journal: Journal of Clinical Oncology (2023)

TPS620 Background: Gallbladder carcinoma (GBC) is a rare disease with a poor prognosis, with an overall estimated 5-year survival rate of 5-13%. Approximately 70% of gallbladder cancers in the US are found incidentally on pathologic analysis after elective cholecystectomy for presumed benign disease. Current management guidelines for incidental gallbladder cancer (IGBC) recommend re-resection for T1b, T2, and T3 lesions, which entails a partial hepatectomy and lymph node dissection. Up to 75% of patients have residual locoregional disease and 20% have disseminated disease at the time of re-resection, both factors strongly associated with poor prognosis and inoperability, respectively. For those who undergo re-resection, the recurrence rate at one year can be as high as 40%. Therefore we designed a Phase II/III trial to assess the benefit of a perioperative chemotherapy approach around the re-resection procedure compared to standard of care adjuvant therapy alone. Methods: We have enrolled 18 of 186 planned patients (Phase III design) on study NCT 04559139/EA2197. Current eligibility criteria include: Incidentally diagnosed T2 / T3 gallbladder cancer with no evidence of metastatic disease or inoperable locoregional disease. At randomization, patients must be within 12 weeks of their index cholecystectomy. Patients are randomized 2:1 to receive perioperative chemotherapy with gemcitabine and cisplatin vs adjuvant therapy alone. The primary endpoint is overall survival. Secondary endpoints include resectability, presence of residual disease, and progression-free survival. Clinical trial information: 04559139 .
BXQ-350: Modulating ceramide and sphingosine-1-phosphate for antitumor activity in patients with advanced CRC.
Authors: Olivier Rixe, Richard Charles Curry, John Charles Morris, Carolyn Muller, Anne M. Noonan, Vinay K. Puduvalli, John L. Villano, Trisha Michel Wise-Draper, Robert Wesolowski, Emrullah Yilmaz, Gilles Tapolsky, Ray Takigiku
Journal: Journal of Clinical Oncology (2023)

154 Background: Sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Many publications have demonstrated that ceramides are proapoptotic, synergize with cancer treatments, and mitigate chemoresistance. Findings also demonstrated that sphingosine-1-phosphate (S1P) is a key sphingolipid that promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies of colorectal cancer patients have shown high levels of ceramides being associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism continues to be a promising treatment approach. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in an all-comer cancer patients with advanced solid malignancies ( NCT02859857 ) to determine its safety profile and potential clinical activity as monotherapy. Samples were collected to explore potential biomarkers. Results: 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 (PR, SD), with the majority experiencing a decrease in systemic S1P levels and an increase in C18 levels. 8 patients (~11% of evaluable patients) had PFS &gt; 6 months, with 2 patients still on study six years after enrollment. Analysis of plasma samples also revealed an increase in anti-tumoral cytokines (IFNg, TNFa, IL-2) and a decrease in pro-tumoral ones (IL-6, 8, 10). Among patients with PFS &gt; 6 months, there were 4 recurrent CRC patients (1PR, 3SD): 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 6 years. Conclusions: Results of this Phase 1 study in heavily pretreated patients show BXQ-350 was well tolerated and seem to generate a clinical benefit in CRC patients via modulation of S1P and ceramides. A phase 2 trial of BXQ-350 in combination with FOLFOX/Bevacizumab in newly diagnosed mCRC is on-going with plans to further investigate this novel mechanism of action. Clinical trial information: 02859857 .
When I use a word . . . . Information
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

Information in common parlance means knowledge communicated about particular facts, subjects, or events; a fact, for example, is a piece of information. However, in computing science information has a different meaning, given by information theory, and is the degree of choice exercised when a particular symbol or message is chosen from a range of possible symbols or messages, the choice being probabilistically determined. The latest outcome of this is the development of GPTs (Generative Pre-trained Transformers), or chatbots, which may facilitate the writing of medical and other scientific texts. The extent to which this may be advantageous or otherwise is not yet clear, but there will certainly be unintended consequences.
Pleiotrophin drives a prometastatic immune niche in breast cancer
Authors: Debolina Ganguly, Marcel O. Schmidt, Morgan Coleman, Tuong-Vi Cindy Ngo, Noah Sorrelle, Adrian T.A. Dominguez, Gilbert Z. Murimwa, Jason E. Toombs, Cheryl Lewis, Yisheng V. Fang, Fatima Valdes-Mora, David Gallego-Ortega, Anton Wellstein, Rolf A. Brekken
Journal: The Journal of Experimental Medicine (2023)

Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-κB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment, and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor-associated neutrophils and reverts local immune suppression, resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade and chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a prometastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.
Personalized care of patients with heart failure: are we ready for a <scp>REWOLUTION</scp>? Insights from two international surveys on healthcare professionals' needs and patients' perceptions
Authors: Ewa A. Jankowska, Peter P. Liu, Martin R. Cowie, Max Groenhart, Kelly D. Cobey, Jonathan Howlett, Michel Komajda, Lars H. Lund, Jose Antonio Magaña Serrano, Ricardo Mourilhe‐Rocha, Giuseppe M.C. Rosano, Clara Saldarriaga, Pedro V. Schwartzmann, Faiez Zannad, Jian Zhang, Yuhui Zhang, Andrew J.S. Coats
Journal: European Journal of Heart Failure (2023)

Guidelines for the management of heart failure (HF) are evolving, and increasing emphasis is placed on patient-centred care. As part of the REWOLUTION HF (REal WOrLd EdUcaTION in HF) programme, we conducted two international surveys aimed at assessing healthcare professionals' (HCPs) educational needs and patients' perspectives on the care of HF.Anonymous online questionnaires co-developed by HF experts and patients assessed HCPs' educational needs (520 respondents, mostly cardiologists, in 67 countries) and patients' perceptions on HF impact and management (98 respondents in 18 countries). Among HCPs, 62.7% prioritized rapid initiation of all guideline-mandated medications over up-titration of some medications, and 87.7% always or frequently discussed treatment goals with patients. There was good agreement between HCPs and patients on key treatment goals, except for a greater emphasis on reducing hospitalizations among HCPs. The most frequently cited barriers to the provision of guideline-recommended pharmacological therapy were treatment side effects/intolerance, complex treatment regimens, low blood pressure, cost/reimbursement issues, and low estimated glomerular filtration rate. Most patients (81.6%) reported no difficulties taking medications as prescribed, although 21.4% felt they were taking too many pills. Patients wanted more information about HF and its consequences, prognosis, and treatments (70.4%, 74.5% and 76.6%, respectively). Cardiologists were the preferred source of information about HF, followed by general practitioners and HF nurses.These surveys provide valuable insights into HCPs' needs about personalized care for patients with HF, as well as patients' perceptions, expectations and preferences. These findings will be helpful to develop patient-centred, needs-driven quality improvement programmes.
Sarcomatous Transformation of a Medically Treated Lactotroph Pituitary Neuroendocrine Tumor?
Authors: Merryl Terry, Gerald Reis, Andrew Horvai, Melike Pekmezci, Arie Perry
Journal: Endocrine Pathology (2023)

This 49-year-old man presented with headaches, diplopia, and elevated serum prolactin (> 2000 ng/mL).Brain MRI revealed a 4.6 cm enhancing mass in the pituitary fossa, with inferolateral invasion.He was treated medically with cabergoline with normalization of prolactin but no improvement in symptoms.He underwent tumor resection.
HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation
Authors: Zhishuo Wang, Chenghua Yan, Qizhen Du, Yuying Huang, Xuezhen Li, Dan Zeng, Ruizhi Mao, Rama Krishna Gurram, Shipeng Cheng, Wangpeng Gu, Lin Zhu, Weiguo Fan, Liyan Ma, Zhiyang Ling, Ju Qiu, Dangsheng Li, Enmei Liu, Yaguang Zhang, Yiru Fang, Jinfang Zhu, Bing Sun
Journal: Cellular and Molecular Immunology (2023)
Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma
Authors: Julio C. Chavez, Francine M. Foss, Basem M. William, Jonathan E. Brammer, Sonali M. Smith, Anca Prica, Jasmine M. Zain, Joseph M. Tuscano, Harsh Shah, Neha Mehta-Shah, Praveen Ramakrishnan Geethakumari, Ben X. Wang, Stephanie Zantinge, Lisa Wang, Ling Zhang, Anmarie Boutrin, Weiguang Zhao, Lily Cheng, Nathan Standifer, Lisa Hewitt, Enowmpey Enowtambong, Weiping Shao, Shringi Sharma, Gianluca Carlesso, Jeffrey A. Moscow, Lillian L. Siu
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Proliferation of T-follicular helper (TFH) CD4+ T cells is a postulated pathogenic mechanism for T-cell non-Hodgkin lymphomas (T-NHL). The inducible T-cell costimulator (ICOS) is highly expressed by TFH, representing a potential target. MEDI-570 is a monoclonal antibody against ICOS, which eliminates ICOS+ cells in preclinical models. Patients and Methods: We report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of MEDI-570 in T-NHL. NCI-9930 is a phase I, first-in-human study of MEDI-570 in relapsed/refractory malignant T-NHL known to express ICOS. MEDI-570 was administered intravenously every 3 weeks for up to 12 cycles. Primary endpoints were safety, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D). Secondary and exploratory endpoints included efficacy parameters and various correlative studies. This study is supported by the National Cancer Institute (NCT02520791). Results: Twenty-three patients were enrolled and received MEDI-570 at five dose levels (0.01–3 mg/kg). Sixteen (70%) had angioimmunoblastic T-cell lymphoma (AITL); median age was 67 years (29–86) and the median prior lines of therapies was 3 (1–16). Most common grade 3 or 4 adverse events were decreased CD4+ T cells (57%), lymphopenia (22%), anemia (13%), and infusion-related reactions (9%). No DLTs were observed. The RP2D was determined at 3 mg/kg. Analysis of T-cell subsets showed reductions in CD4+ICOS+ T cells reflecting its effects on TFH cells. The response rate in AITL was 44%. Conclusions: MEDI-570 was well tolerated and showed promising clinical activity in refractory AITL. MEDI-570 resulted in sustained reduction of ICOS+ T lymphocytes.
Implementing pragmatic clinical trials in hepatology
Authors: Elliot B. Tapper, Marina Serper, David S. Goldberg
Journal: Hepatology (2023)

Patients with chronic liver disease would benefit from pragmatic trial designs. A pragmatic trial seeks to inform clinical decision-making by providing evidence for the adoption of an intervention into real-world clinical practice. A trial’s pragmatism is based on the efficiency by which it identifies, recruits, and follows patients, the degree to which the interventions and design mirror the usual clinical care, and the importance of the outcomes to the patients. We review the promise, trade-offs, and purpose of pragmatic trials in hepatology.
Multiomic spatial analysis reveals a distinct mucosa-associated virome
Authors: Austin Yan, James Butcher, Laetitia Schramm, David R. Mack, Alain Stintzi
Journal: Gut Microbes (2023)

The human gut virome has been increasingly explored in recent years. However, nearly all virome-sequencing efforts rely solely on fecal samples and few studies leverage multiomic approaches to investigate phage–host relationships. Here, we combine metagenomics, metaviromics, and metatranscriptomics to study virome-bacteriome interactions at the colonic mucosal-luminal interface in a cohort of three individuals with inflammatory bowel disease; non-IBD controls were not included in this study. We show that the mucosal viral population is distinct from the stool virome and houses abundant crAss-like phages that are undetectable by fecal sampling. Through viral protein prediction and metatranscriptomic analysis, we explore viral gene transcription, prophage activation, and the relationship between the presence of integrase and temperate phages in IBD subjects. We also show the impact of deep sequencing on virus recovery and offer guidelines for selecting optimal sequencing depths in future metaviromic studies. Systems biology approaches such as those presented in this report will enhance our understanding of the human virome and its interactions with our microbiome and our health.
Intensive versus standard blood pressure control in older persons with or without diabetes: a systematic review and meta-analysis of randomised controlled trials
Authors: Samuel Seidu, Harini Willis, Setor K Kunutsor, Kamlesh Khunti
Journal: Journal of the Royal Society of Medicine (2023)

Objectives To assess and compare the benefits and harms of intensive versus standard blood pressure (BP) control in older people with or without diabetes mellitus (DM). Design Systematic review and meta-analysis Setting Randomised controlled trials comparing intensive versus standard BP control, identified from MEDLINE, Embase, The Cochrane library, Web of Science and a search of bibliographies from inception till August 2022. Participants Older people (≥65 years) with or without DM. Main outcome measures Study-specific risk ratios (RRs) with 95% confidence intervals (CIs) were pooled for adverse vascular and safety outcomes. Results We included six randomised controlled trials (RCTs) comprising 20,985 patients (intensive BP = 10,474 and standard BP = 10,511) with a weighted mean follow-up of 3.1 years. In the general population, the RRs (95% CIs) of intensive versus standard BP control for composite cardiovascular events or major adverse cardiovascular events (CVD/MACE), CVD mortality, coronary heart disease, stroke and heart failure were 0.71 (0.62–0.82), 0.65 (0.49–0.86), 0.75 (0.60–0.95), 0.75 (0.61–0.92) and 0.58 (0.41–0.82), respectively. Intensive BP control did not increase the risk of renal failure or serious adverse events in the general population. Two RCTs reported results for composite CVD/MACE in patients with DM with a pooled estimate of 0.85 (0.67–1.07). Conclusions Aggregate trial evidence shows that intensive BP control (&lt;120 to &lt;140 mmHg) reduces the risk of adverse cardiovascular outcomes in older hypertensive patients in the general population with no increase in adverse events. Intensive BP control may confer similar benefits for older patients with DM with no evidence for harm, but this is based on limited data. PROSPERO Registration: CRD42022349791